The purpose of this project is to study the role of the immune system in connective tissue metabolism. Studies examining the events involved in macrophage activation which lead to the production of collagenase have focused on the role of the ornithine decarboxylase (ODC) pathway. Our findings demonstrate that a significant inhibition of LPS-induced ODC occurs when macrophages are exposed to indomethacin or difluoromethyl ornithine, a specific inhibitor of ODC. These agents also block collagenase production, implicating ODC in the activation by macrophages. Immune regulation of bone metabolism has been studied in osteopetrotic (op) rats and in rats in which rickets has been induced by a vitamin D deficient diet. Thymocytes from op rats were suppressed in their proliferative response when compared to normal littermates. Separation of the thymocytes into subpopulations by counterflow centrifugal elutriation demonstrated a subset of op cells which proliferated when stimulated. Studies of the immune function of normal and rachitic rats revealed that the lack of vitamin D results in a significant decrease in the proliferative capacity of thymocytes. Macrophage function is also affected as evidenced by a significant inhibition of in vivo and in vitro chemotaxis.